A Case Series Demonstrating the Difficulties in Diagnosing COVID-19 Associated Pulmonary Aspergillus.

Many bacterial, viral, and fungal co-infections have been reported with COVID-19-associated acute respiratory distress syndrome (ARDS). Invasive Aspergillosis has been described with COVID-19 ARDS. However, it continues to evade diagnosis in critically ill patients admitted to the intensive care unit (ICU). The difficulty is discerning an actual infection from colonization. Unfortunately, a timely diagnosis is crucial since COVID-19-associated pulmonary Aspergillus (CAPA) has high morbidity and mortality. We present three ICU cases of CAPA to illustrate the difficulty in diagnosing and treating the disease. We hope to bring awareness and improve patient outcomes of CAPA.

A return to 1992: Using the "blowhole" technique for diffuse subcutaneous emphysema caused by a broncho-pleural fistula.

A bronchopleural fistula (BPF) is an abnormal communication between the bronchial tree and pleural space resulting in a high risk for morbidity and mortality. We describe a case highlighting the management of a BPF with subcutaneous and mediastinal air resulting in dysphagia and dysphonia using a technique that was first described in a 1992 CHEST article. The "Blowhole" technique may be utilized for patients that are poor surgical candidates requiring rapid correction and prevention of detrimental consequences such as pneumomediastinum, tension pneumothorax, upper airway compromise and pneumopericardium.

Pause at Your Own Peril: A Case Series on Rebound Pulmonary Hypertension.

Severe pulmonary arterial hypertension (PAH) is associated with high morbidity and mortality. Therapeutic approaches for intermediate- and high-risk pulmonary arterial hypertension have now shifted toward initial combination management, often including parenteral epoprostenol and iloprost and early assessment for a lung transplant. After the initiation of therapy, usually various combinations of different classes of medication, it is important to consider the potential interruption in therapy causing rebound PAH. We present two patients recently admitted to our hospital with rebound symptoms after interruption of their pulmonary vasodilator therapy.

Aerococcus urinae tricuspid valve infective endocarditis.

Aerococcus urinae is an alpha-hemolytic, gram-positive coccus that is responsible for 54/1,000,000 cases of all urinary tract infections. Risk factors include male gender, advanced age, and genitourinary tract abnormalities. It has often been misidentified as Staphylococcus or Streptococcus due to its morphological similarities. Fewer than 50 cases of A. urinae infective endocarditis have been reported, most affecting the mitral or aortic valve. We present the case of a 61-year-old woman who presented with recurrent fevers and worsening dyspnea on exertion and was found to have A. urinae bacteremia. A transesophageal echocardiogram showed evidence of moderate tricuspid valve regurgitation and vegetations involving its posterior and septal leaflets. The patient was successfully treated with intravenous penicillin G for 6 weeks. She was not deemed a candidate for cardiac surgery.

Seeds in the Lungs: A Pseudo-Miliary Pattern of Sarcoidosis.

We present a 26-year-old African-American gentleman with no significant past medical history who presented with a three-day history of dry cough. Computerized tomography of the chest showed scattered infiltrates consistent with a pseudo-miliary pattern. A transbronchial biopsy showed non-caseating granulomas confirming our suspicion for pulmonary sarcoidosis. Miliary sarcoidosis is rare; therefore, health care providers should consider other diagnoses such as tuberculosis, malignancy, and pneumoconiosis.

Calcium Carbonate (Tums)-Associated Hypercalcemic Crisis.

Hypercalcemic crisis due to severe decompensated hypercalcemia represents a life-threatening medical emergency leading to renal failure and altered mental status. Hypercalcemic crisis most commonly results from hypercalcemia of malignancy, undiagnosed primary hyperparathyroidism, granulomatous diseases, and medication-induced hypercalcemia. Commonly prescribed medications like thiazide diuretics, lithium therapy, and teriparatide are among the medications known to cause hypercalcemia. Here, we describe a case of the hypercalcemic crisis caused by excessive calcium carbonate ingestion emphasizing physicians to be aware of this potentially life-threatening adverse effect of a widely available over-the-counter acid reflux medication and educate patients regarding the same.

Transudative pleural effusion as an initial presentation of a disseminated cryptococcosis infection in a HIV-negative patient with cirrhosis.

To our knowledge, this is the first case report of a transudative pleural effusion with positive Cryptococcal antigen and culture. We describe a 32-year-old male with end-stage liver disease (ESLD) who presented to an outside hospital with dyspnea and a large pleural effusion. An initial pleural fluid analysis was positive for Cryptococcal Ag. However, the infection was eventually found to be widespread as he had positive Cryptococcal Ag and cultures in his pleural fluid, serum, and cerebrospinal fluid (CSF). His antimicrobial regiment was escalated from fluconazole to amphotericin B and flucytosine. His medical condition deteriorated, and the patient passed away. Due to its rarity and range of clinical severity, diagnosis of disseminated Cryptococcosis can be delayed. We present this case to bring awareness of this diagnosis as a differential in immunocompromised patients regardless of a transudative pleural effusion.

Evidence that 5-HT stimulates intracellular Ca2+ signalling and activates pannexin-1 currents in type II cells of the rat carotid body.

KEY POINTS: 5-HT is a neuromodulator released from carotid body (CB) chemoreceptor (type I) cells and facilitates the sensory discharge following chronic intermittent hypoxia (CIH). In the present study, we show that, in addition to type I cells, adjacent glial-like type II cells express functional, ketanserin-sensitive 5-HT2 receptors, and their stimulation increases cytoplasmic Ca2+ derived from intracellular stores. In type II cells, 5-HT activated a ketanserin-sensitive inward current (I5-HT ) that was similar to that (IUTP ) activated by the P2Y2R agonist, UTP. As previously shown for IUTP , I5-HT was inhibited by BAPTA-AM and carbenoxolone (5 µm), a putative blocker of ATP-permeable pannexin (Panx)-1 channels; IUTP was reversibly inhibited by the specific Panx-1 mimetic peptide channel blocker, 10 Panx peptide. Paracrine stimulation of type II cells by 5-HT, leading to ATP release via Panx-1 channels, may contribute to CB excitability, especially in pathophysiological conditions associated with CIH (e.g. obstructive sleep apnoea). ABSTRACT: Carotid body (CB) chemoreceptor (type I) cells can synthesize and release 5-HT and increased autocrine-paracrine 5-HT2 receptor signalling contributes to sensory long-term facilitation during chronic intermittent hypoxia (CIH). However, recent studies suggest that adjacent glial-like type II cells can respond to CB paracrine signals by elevating intracellular calcium (Δ[Ca2+ ]i ) and activating carbenoxolone-sensitive, ATP-permeable, pannexin (Panx)-1-like channels. In the present study, using dissociated rat CB cultures, we found that 5-HT induced Δ[Ca2+ ]i responses in a subpopulation of type I cells, as well as in most (∼67%) type II cells identified by their sensitivity to the P2Y2 receptor agonist, UTP. The 5-HT-induced Ca2+ response in type II cells was dose-dependent (EC50 ∼183 nm) and largely inhibited by the 5-HT2A receptor blocker, ketanserin (1 µm), and also arose mainly from intracellular stores. 5-HT also activated an inward current (I5-HT ) in type II cells (EC50 ∼200 nm) that was reversibly inhibited by ketanserin (1-10 nm), the Ca2+ chelator BAPTA-AM (5 µm), and low concentrations of carbenoxolone (5 µm), a putative Panx-1 channel blocker. I5-HT reversed direction at approximately -11 mV and was indistinguishable from the UTP-activated current (IUTP ). Consistent with a role for Panx-1 channels, IUTP was reversibly inhibited by the specific Panx-1 mimetic peptide blocker 10 Panx (100 µm), although not by its scrambled control peptide (sc Panx). Because ATP is an excitatory CB neurotransmitter, it is possible that the contribution of enhanced 5-HT signalling to the increased sensory discharge during CIH may occur, in part, by a boosting of ATP release from type II cells via Panx-1 channels.

Purinergic signalling mediates bidirectional crosstalk between chemoreceptor type I and glial-like type II cells of the rat carotid body.

KEY POINTS: Carotid body chemoreceptors are organized in clusters containing receptor type I and contiguous glial-like type II cells. While type I cells depolarize and release ATP during chemostimulation, the role of type II cells which express purinergic P2Y2 receptors (P2Y2Rs) and ATP-permeable pannexin-1 (Panx-1) channels, is unclear. Here, we show that in isolated rat chemoreceptor clusters, type I cell depolarization induced by hypoxia, hypercapnia, or high K(+) caused delayed intracellular Ca(2+) elevations (Δ[Ca(2+)]i) in nearby type II cells that were inhibited by the P2Y2R blocker suramin, or by the nucleoside hydrolase apyrase. Likewise, stimulation of P2Y2Rs on type II cells caused a delayed, secondary Δ[Ca(2+)]i in nearby type I cells that was inhibited by blockers of Panx-1 channels, adenosine A2A receptors and 5'-ectonucleotidase. We propose that reciprocal crosstalk between type I and type II cells contributes to sensory processing in the carotid body via purinergic signalling pathways. ABSTRACT: The mammalian carotid body (CB) is excited by blood-borne stimuli including hypoxia and acid hypercapnia, leading to respiratory and cardiovascular reflex responses. This chemosensory organ consists of innervated clusters of receptor type I cells, ensheathed by processes of adjacent glial-like type II cells. ATP is a major excitatory neurotransmitter released from type I cells and type II cells express purinergic P2Y2 receptors (P2Y2Rs), the activation of which leads to the opening of ATP-permeable, pannexin-1 (Panx-1) channels. While these properties support crosstalk between type I and type II cells during chemotransduction, direct evidence is lacking. To address this, we first exposed isolated rat chemoreceptor clusters to acute hypoxia, isohydric hypercapnia, or the depolarizing stimulus high K(+), and monitored intracellular [Ca(2+)] using Fura-2. As expected, these stimuli induced intracellular [Ca(2+)] elevations (Δ[Ca(2+)]i) in type I cells. Interestingly, however, there was often a delayed, secondary Δ[Ca(2+)]i in nearby type II cells that was reversibly inhibited by the P2Y2R antagonist suramin, or by the nucleoside hydrolase apyrase. By contrast, type II cell stimulation with the P2Y2R agonist uridine-5'-triphosphate (100 µm) often led to a delayed, secondary Δ[Ca(2+)]i response in nearby type I cells that was reversibly inhibited by the Panx-1 blocker carbenoxolone (5 µm). This Δ[Ca(2+)]i response was also strongly inhibited by blockers of either the adenosine A2A receptor (SCH 58261) or of the 5'-ectonucleotidase (AOPCP), suggesting it was due to adenosine arising from breakdown of ATP released through Panx-1 channels. Collectively, these data strongly suggest that purinergic signalling mechanisms mediate crosstalk between CB chemoreceptor and glial cells during chemotransduction.

Paracrine Signaling in Glial-Like Type II Cells of the Rat Carotid Body.

The carotid body (CB) chemosensory complex uses ATP as a key excitatory neurotransmitter that is the main contributor to the sensory discharge during acute hypoxia. The complex includes receptor type I cells, which depolarize and release various neurochemicals including ATP during hypoxia, and contiguous glial-like type II cells which express purinergic P2Y2 receptors (P2Y2R). We previously showed that activation of P2Y2R on rat type II cells led to the opening of pannexin-1 (Panx-1) channels, which acted as conduits for the further release of ATP. More recently, we considered the possibility that other CB neuromodulators may have a similar paracrine role, leading to the activation of type II cells. Here, we examine the evidence that angiotensin II (ANG II), endothelin- (ET-1), and muscarinic agonists (e.g. acetylcholine, ACh) may activate intracellular Ca(2+) signals in type II cells and, in the case of ANG II and ACh, Panx-1 currents as well. Using ratiometric Ca(2+) imaging, we found that a substantial population of type II cells responded to 100 nM ANG II with a robust rise in intracellular Ca(2+) and activation of Panx-1 current. Both effects of ANG II were mediated via AT(1) receptors (AT(1)Rs) and current activation could be inhibited by the Panx-1 channel blocker, carbenoxolone (CBX; 5 µM). Additionally, low concentrations of ET-1 (1 nM) evoked robust intracellular Ca(2+) responses in subpopulations of type II cells. The mAChR agonist muscarine (10 µM) also induced a rise in intracellular Ca(2+) in some type II cells, and preliminary perforated-patch, whole-cell recordings revealed that ACh (10 µM) may activate Panx-1-like currents. These data suggest that paracrine activation of type II cells by endogenous neuromodulators may be a common feature of signal processing in the rat CB.